Phosphotidylinositol (PtdIns) signaling is tightly regulated both spatially and temporally by subcellularly localized PtdIns kinases and phosphatases that dynamically alter downstream signaling events1. Joubert syndrome is characterized by a specific midbrain-hindbrain malformation ('molar tooth sign'), variably associated retinal dystrophy, nephronophthisis, liver fibrosis and polydactyly2 and is included in the newly emerging group of 'ciliopathies'. In individuals with Joubert disease genetically linked to JBTS1, we identified mutations in the INPP5E gene, encoding inositol polyphosphate-5-phosphatase E, which hydrolyzes the 5-phosphate of PtdIns(3,4,5)P3 and PtdIns(4,5)P2. Mutations clustered in the phosphatase domain and impaired 5-phosphatase activity, resulting in altered cellular PtdIns ratios. INPP5E localized to cilia in major organs affected by Joubert syndrome, and mutations promoted premature destabilization of cilia in response to stimulation. These data link PtdIns signaling to the primary cilium, a cellular structure that is becoming increasingly recognized for its role in mediating cell signals and neuronal function.
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We thank the Marshfield Clinic Research Foundation, Center for Inherited Disease Research and University of California Los Angeles Microarray Core (supported by the US National Heart, Lung, and Blood Institute and National Institutes of Health) for genotyping support. J. Meerloo at the University of California San Diego (UCSD) Neuroscience Microscopy Imaging Core (P30NS047101) provided imaging support. Ryan Anderson of the UCSD Material Sciences provided electron microscopy support. We thank members of the the Dixon lab (UCSD) for suggestions and help with protein modeling, and members of the Mitchell lab (Monash University) for reagents. This work was supported by the UCSD Neuroplasticity of Aging Training Grant (to S.L.B.), the Italian Ministry of Health (RC2008 to B.D., Ricerca Finalizzata 2006 to E.M.V.), the Telethon Foundation Italy (GGP08145 to E.B. and E.M.V.), National Institutes of Health grant HL 16634 (to P.W.M. and M.V.K.), American Heart Association grant 0730350N (to M.V.K.), the National Institute of Neurological Disorder and Stroke, the Burroughs Welcome Fund, the March of Dimes and the Howard Hughes Medical Institute (to J.G.G.).
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